Amphotericin B products are used to treat a variety of fungal infections, including systemic fungal infections.
However, amphotericin B induces serious adverse reactions. This background will describe the amphotericin B adverse reactions, discovery of a mechanism for the adverse reactions, and a description of markers of these reactions.
Amphotericin B is used primarily an intravenous agent in the treatment of severe fungal infections. However, its usefulness is compromised by a high incidence of adverse effects [flu-like symptoms (fever, chills, myalgias), capillary leak syndrome (hypotension, decreased organ perfusion), pulmonary congestion, changes in mental status (lethargy, confusion, agitation), renal dysfunction with secondary hypokalemia, hypomagnesemia and anemia, and liver dysfunction]. These adverse reactions are observed in up to seventy percent of treated patients. The mechanisms responsible for these reactions are, to date, not entirely known.
Through molecular biologic techniques, the present inventors have discovered inflammatory cytokine genes that are up-regulated (increased in cells) after exposure to amphotericin B. The genes include interleukin-1, a potent inflammatory cytokine. The adverse effects associated with stimulation of interleukin-1 are discussed below.
Proposed mechanisms of amphotericin B induced “flu like syndrome” include the expression of interleukin-1 (IL-1), tumor necrosis factor (TNF) or prostaglandins by mononuclear cells which then alter the hypothalamic set point inducing fever and chills. Administration of endotoxin causes similar reactions. Amphotericin B-exposed mononuclear cells induces unique morphological changes and dramatically altered protein expression. Some host cell proteins have been reported to be inducible by amphotericin B, such as TNF-α and IL-1β. The present inventors have demonstrated that this protein expression is not associated with release of preformed protein; protein release is associated with up-regulation of a gene or derepression of an inhibitory gene.
Currently, pharmacologic agents used to prevent amphotericin B adverse reactions only address small aspects of the problem. Hydrocortisone is used to prevent the flu-like syndrome and hypotension. Acetaminophen is also used to prevent the flu-like syndrome. Fluids administered parenterally are used to prevent renal dysfunction. Also, lipid products have been developed to decrease the toxicity of amphotericin B. These products encapsule or protect amphotericin B from causing these reactions. However, they are not totally successful.
What is needed, then, is an amphotericin B product and treatment method without the high incidence of side effects.